Method for preparing 2-thienylethylamine derivatives

Abstract

PCT No. PCT/FR98/00441 Sec. 371 Date Sep. 2, 1999 Sec. 102(e) Date Sep. 2, 1999 PCT Filed Mar. 5, 1998 PCT Pub. No. WO98/39322 PCT Pub. Date Sep. 11, 1998The present invention relates to a process for the preparation of 2-thienylethylamine derivatives of general formula: as well as their acid addition salts, in which R represents a halogen atom and R1 represents a C1-C4 alkyl group, characterized in that a thienylglycidic derivative of general formula: in which M represents an alkali metal atom or a fraction of an alkaline-earth metal atom, is reacted with a phenylglycine ester, optionally in the form of a strong acid salt, of general formula: in which R and R1 have the same meaning as above, in the presence of an alkali metal borchydride of general formula: X-YIV in which X represents an alkali metal atom and Y represents a group of formula: -BH3CN or -BH(4-w)Zw in which Z represents a carboxylic acid residue and optionally in the presence of a C1-C4 carboxylic acid, which gives the desired compound in the form of a free base which can be treated, if necessary, with an acid in order to obtain an addition salt of this compound.

What is claimed is: 
     
       1. Process for the preparation of 2-thienylethylamine derivatives of general formula: ##STR8## as well as their acid addition salts, in which R represents a halogen atom and R 1  represents a C 1  -C 4  alkyl group wherein a thienylglycidic derivative of general formula: ##STR9## in which M represents an alkali metal atom or a fraction of an alkaline-earth metal atom, is reacted with a phenylglycine ester, optionally in the form of a strong acid salt, of general formula: ##STR10## in which R and R 1  have the same meaning as above, in the presence of an alkali metal borohydride of general formula:   X--Y                                                       IV     in which X represents an alkali metal atom and Y represents a group of formula:     --BH.sub.3 CN or --BH.sub.(4-w) Z.sub.w     in which Z represents a carboxylic acid residue and w represents 1, 2 or 3, which gives the desired compound in the form of a free base which can be treated, if necessary, with an acid in order to obtain an addition salt of this compound.   
     
     
       2. Process according to claim 1 wherein the halogen atom is situated at the ortho position. 
     
     
       3. Process according to claim 1 wherein the halogen atom is chlorine. 
     
     
       4. Process according to claim 3 wherein R 1  represents methyl. 
     
     
       5. Process according to claim 4 wherein the 2-thienylethylamine derivative of formula I and the phenylglycine ester of formula III are each in (+)-(S) enantiomer form. 
     
     
       6. Process according to claim 1 wherein M represents lithium, sodium, potassium, calcium 1/2 or magnesium 1/2. 
     
     
       7. Process according to claim 1 wherein the phenylglycine ester of formula III is in the form of a strong acid salt chosen from hydrochloride or methanesulphonate. 
     
     
       8. Process according to claim 1 wherein Z represents a carboxylic acid residue of general formula:   R.sub.2 --CO.sub.2 --     in which R 2  represents a C 1  -C 10  alkyl group.   
     
     
       9. Process according to claim 1 wherein the alkali metal borohydride corresponds to sodium cyanoborohydride. 
     
     
       10. Process according to claim 9 wherein the reaction is carried out in the presence of a C 1  -C 4  alkylcarboxylic acid. 
     
     
       11. Process according to claim 10 wherein the carboxylic acid is used at a concentration not exceeding 0.50 mol/l. 
     
     
       12. Process according to claim 11 wherein the carboxylic acid is used at a concentration of 0.30 to 0.35 mol/l. 
     
     
       13. Process according to claim 9 wherein the carboxylic acid is acetic acid. 
     
     
       14. Process according to claim 9 wherein the phenylglycine ester of formula III is in the form of a strong acid salt. 
     
     
       15. Process according to claim 1 wherein the thienylglycidic derivative of formula II is used in excess, up to an additional 0.5 mol per mol of phenylglycine ester of formula III. 
     
     
       16. Process according to claim 1 wherein the alkali metal borohydride coresponds to a compound of formula IV in which Y represents the --BH.sub.(4-w) Z w  group. 
     
     
       17. Process according to claim 16 wherein the reaction is carried out in a C 1  -C 4  alkylcarboxylic acid. 
     
     
       18. Process according to claim 16 wherein the phenylglycine ester of formula III is used in excess up to 2.2 molar equivalents per molar equivalent of thienylglycidic derivative of formula II. 
     
     
       19. Process according to claim 1 wherein the alkali metal borohydride of formula IV is used at a concentration not exceeding 0.40 mol/l. 
     
     
       20. Process according to claim 5 wherein methyl (+)-(S)-α-(2-thienyl-2-ethylamino)-α-(2-chlorophenyl)acetate is prepared.